Nicotinic acetylcholine receptors (nAChRs) or Neuronal nicotinic receptors (NNRs) mediate a very wide range of physiological effects and have been targeted for therapeutic treatment of various disorders. nAChRs belonging to the super family of ligand gated ion channels (LGIC), are widely distributed throughout the central nervous system (CNS) and the peripheral nervous system (PNS). The NNRs are understood to play an important role in regulating CNS function and the release of many neurotransmitters. Typically, NNRs are constructed from a pentameric assembly of subunit proteins. Seventeen subunits of nAChRs have been identified to date, which are identified as α2-α18, β1-β4, γ, δ, and ε. Of these subunits, eight neuronal α (α2 through α9) and three neuronal β (β2 through β4), prominently exist in the mammalian brain. (See for examples, Monteggia L M et al., Cloning and transient expression of genes encoding the human alpha4 and beta2 neuronal nicotinic acetylcholine receptor (nAChR) subunits, Gene: 1995, 155:189-193; Graham A et al., Immunohistochemical localization of nicotinic acetylcholine receptor subunits in human cerebellum, Neuroscience. 2002; 113:493-507). Multiple functionally distinct nAChR complexes also exist; as a homomeric functional pentamer or combinations of different subunits can complex together (see for examples, Hogg, R. C et al., Nicotinic acetylcholine receptors: from structure to brain function, Rev. Physiol, Biochem. Pharmacol, 2003, 147: 1-46).
The identification of a family of genes coding for the nAChRs and increased knowledge of their expression and function in the central nervous system have lead to the increasing attention concerning their potential as drug targets. (See examples, Hogg R. C et al., Nicotinic Acetylcholine Receptors as Drug Targets, Curr. Drug Targets: CNS Neurol. Disord. 2004, 3: 123-130; Suto et al., Neuronal nicotinic acetylcholine receptors as drug targets, Expert Opin. Ther. Targets 2004, 8: 61-64).
There are many potential therapeutic uses for neuronal nicotinic α4β2 receptor ligands in humans based on direct effects and on indications from available scientific studies. Neuronal nicotinic α4β2 receptors have been implicated in different therapies like cognitive disorders, including Alzheimer's disease, Parkinson's disease, Attention deficit/hyperactivity disorder, Schizophrenia and Tourette's syndrome (See examples, Newhouse et al., Effects of nicotinic stimulation on cognitive performance, Curr. Opin. Pharmacol. 2004, 4: 36-46; Levin E. D et al., Nicotinic Treatment for Cognitive Dysfunction, Curr. Drug Targets: CNS Neurol. Disord. 2002, 1: 423-431; Graham A. J. et al., Human Brain Nicotinic Receptors, their Distribution and Participation in Neuropsychiatric Disorders, Curr. Drug Targets: CNS Neurol. Disord. 2002, 1: 387-397; McEvoy J. P et al., The Importance of Nicotinic Acetylcholine Receptors in Schizophrenia, Bipolar Disorder and Tourette's Syndrome, Curr. Drug Targets: CNS Neurol. Disord. 2002, 1: 433-442).
Studies in a variety of rodent pain models have demonstrated that α4β2 receptor ligands have the potential for highly efficacious treatments in a variety of pain states and inflammation. (See examples, Vincler et al., Neuronal nicotinic receptors as targets for novel analgesics, Expert Opin. Invest. Drugs, 2005, 14: 1191-1198; Decker M W et al., The therapeutic potential of nicotinic acetylcholine receptor agonists for pain control, Expert Opin Investig Drugs. 2001 October; 10(10):1819-30; Miao et. al., Central terminals of nociceptors are targets for nicotine suppression of inflammation, Neuroscience 2004, 123: 777-84).
Significant efforts are being made to understand the hypercholinergic neurotransmission, which is associated with depressed mood states suggesting that it may be mediated through excessive neuronal nicotinic receptor activation and that the therapeutic actions of many antidepressants may be, in part, mediated through inhibition of these receptors. Thus the neuronal nicotinic α4β2 receptor ligands may represent a novel class of therapeutic agents for treating depression and anxiety disorders (See examples, Shytle et al., Nicotinic acetylcholine receptors as targets for antidepressants, Mol. Psychiatry. 2002, 7: 525-35; Shytle et al., Neuronal nicotinic receptor inhibition for treating mood disorders: preliminary controlled evidence with mecamylamine, Depress. Anxiety, 2002, 16: 89-92). Recent studies have also been reported that the nAChRs play a role in neurodegenerative disorders. The nicotine and subtype selective nAChR ligands can provide neuroprotection in in-vitro cell culture systems and in in-vivo studies in animal models of such disorders. (See examples, O'Neill et al., The role of neuronal nicotinic acetylcholine receptors in acute and chronic neurodegeneration, Curr. Drug Targets: CNS Neurol. Disord. 2002, 1: 399-411).
The α4β2 nAChR subtype has the highest affinity for nicotine and is the primary candidate for mediating nicotine's central effects. Chronic nicotine exposure (in humans, animals and cell culture systems) leads to an increase in the number of α4β2 nAChR (upregulation), with functional implications for withdrawal. These studies suggested that the neuronal nicotinic α4β2 receptor ligands play a critical role in the treatment of addiction. (Dwoskin et al., A novel mechanism of action and potential use for lobeline as a treatment for psychostimulant abuse, Biochem. Pharmacol. 2002, 63: 89-98; Coe et al., 3,5-Bicyclic aryl piperidines: a novel class of α4β2 nAChR partial agonists for smoking cessation, Bioorg. Med. Chem. Lett. 2005, 15: 4889-97). The α4β2 receptor ligands are also expected to be of use in the treatment of obesity (Li et al., Nicotine, body weight and potential implications in the treatment of obesity, Curr. Top. Med. Chem. 2003, 3: 899-919).
Taken together, the above studies strongly suggest that compounds which are α4β2 receptor modulators, i.e. ligands, may be useful for therapeutic indications including, the treatment of diseases associated with a deficit in memory, cognition and learning such as Alzheimer's and attention deficit disorder; the treatment of personality disorders such as schizophrenia; the treatment of behavioral disorders, e.g. anxiety, depression and obsessive compulsive disorders; the treatment of pain and inflammation; the treatment of motion or motor disorders such as Parkinson's disease and epilepsy; the treatment of diseases associated with neurodegeneration such as stroke or head trauma or withdrawal from drug addiction including addiction to nicotine, alcohol and other substances of abuse and obesity.
Patent publications WO2008057938 (A1), US20040192673 (A1) and EP296560 (B1) disclose series of compounds as ligands of nicotinic acetylcholine receptors and are claimed to be useful in the treatment of various CNS disorders. While some nicotinic acetylcholine receptor compounds have been disclosed, there continues to be a need for compounds that are useful for modulating nicotinic acetylcholine receptors. In our research in area of nicotinic acetylcholine receptors, we found that bicyclic compounds of formula (I) demonstrate very high nicotinic acetylcholine receptor affinity. Therefore, it is an object of this invention to provide compounds, which are useful as therapeutic agents in the treatment/prevention of a variety of central nervous system disorders or disorders affected by the α4β2 nicotinic receptors.